Certain 2-alkyl-3-phenyl-5,6-dihydroimidazo(2,1-b)thiazoles

ABSTRACT

SUBSTITUTED IMIDAZOTHIAZOLES,E.G., 3-(4&#39;&#39;-CHLOROPHENYL)2 - ETHYL - 3 - HYDROXY - 5,6 - DIHYDROIMIDAZO(2,1-B) THIAZOLE ARE PREPARED FROM 2-HALOALKYPHENONES AND 2IMIDAZOLINETHIONE AND ARE USEFUL AS ANOREXICS AND ANTIDEPRESENTS.

Patented Apr. 23, 1974 United States Patent Office 38065151 I CERTAINZ-ALKYIh-Pl-IENYL-Sfi-DIHYDRO- IMIDAZO[2,1-b]THIAZOLES William I.Houlihau, 1 Lambrechtgasse, 2500 Baden,

Laurel Hill Road,

8 Claims ABSTRACT OF THE DISCLOSURE Substituted imidazo thiazoles, e.g.,3-(4-chlorophenyl)- 2 ethyl 3 hydroxy 5,6 dihydroimidazo[2,l-b] thiazoleare prepared from 2-haloalkylphenones and 2- imidazolinethione and areuseful as anorexics and antidepressants. i i a This application is acontinuation-in-part of US. application Ser. No. 5,894, filed Jan. 26,1970, which issued as US. Pat. 3,671,533 on June 20, 1972 which in turnis a continuation-in-part of application Ser. No. 790,449, filed Jan.10, 1969, now abandoned, which in turn was a continuation-in-part ofapplication Ser. No. 748,929, filed July 31, 1968, now abandoned. t

This invention relates to novel heterocyclic compounds. Morespecifically it relates to novel 2-alkyl-3-substituted phenyl 5,6dihydroimidazo thiazoles, intermediates therefor, acid addition saltsthereof, and processes for their preparation.

The thiazoles of the present invention may be represented by the formulawhere R represents straight chain lower alkyl, i.e:, straight chainalkyl having 1 to 4 carbon atoms such as methyl, ethyl and propyl; I

R R and R each independently represents hydrogen or halogen having anatomic weight of about 19 to 36;

A is H, and B is OH or A and B together represent a carbon to carbondouble bond, provided at least one of R R and R is other;

where A and B represent a carbon to carbon bond may be represented asfollows:

s I s OH H l-- (Ib) (I where R R R and R have the above statedsignificance.

The thiazoles of Formula Ia are prepared from the compounds of FormulaIb or an acid addition salt thereof by treatment with an acid such ashydrochloric acid, hydrobromic acid or acetic acid (preferably aceticacid) at a temperature from about room temperature to about the refluxtemperature of the system, preferably 50 C. to the reflux temperature.The reaction is normally carried out in excess acid, but a solvent maybe used and the particular solvent utilized is not considered critical.Solvents which may be used are lower alkanols such as ethanol,isopropanol and the like, acetone, tetrahydrofuran, or similar inertsolvents.

When the compounds of Formula Ia are in the form of acid addition salts,they may be converted to the free base by conventional methods such assuspending the salt form in water and adding sodium carbonate.

The 3 hydroxy imidazo[2,l-b]thiazoles of Formula Ib may be prepared inacid addition salt form Ic in accordance with the following reactionscheme:

I X R where R R R and R have the above stated significance and X is Bror Cl.

The 3-hydroxy imidazo[2,1-b]thiazoles of Formula Ic are prepared byhalogenating an alkyl phenyl ketone (V), e.g., 4-chlorobutyrophenone,with bromine or chlorine (IV) in an inert solvent such as chloroform,carbon tetrachloride, methylenechloride or the like, at a temperature of0-50 C. (preferably 20-35 C.) for about 1 to 8 hours. The resulting2-haloalkylphenone (III) is treated with 2-imidazolinethione (II) in aninert solvent such as acetone or lower alkanols having 1 to 5 carbonatoms, e.g., methanol, ethanol or isopropanol, at a temperature of 20-50C. (preferably 25-35 C.) for about 3 to 48 following structural formulaN R.-/ ll s :l

l H N R. H 1) where R R R and R have the above-stated significance, andit should be appreciated that these tautomers can exist in equilibrium.The predominant tautomer is believed to depend on such factors aswhether the compound is a solid or in solution, and the pH and polarityof the environment. In order to simplify thisdescription, however,Formula Ib only will be used, although both tautomeric forms areconsidered to be within the concept-of the present invention.

It is further recognized that the compounds of Formula Ib exist asgeometric and optical isomers, the separation and recovery of which maybe accomplished employing conventional techniques. All of these isomers(geometric and optical) are included within the scope of this invention.

Certain of the compounds of Formula V are known and are prepared bymethods disclosed in the literature. Those not specifically disclosedare prepared from known mate rials using analogous methods.

The compounds of Formula Ia and lb are useful because they possesspharmacological activity in animals. More particularly, the compoundspossess CNS stimulant activity and are useful as anti-depressants asindicated by their activity in the mouse given parenterally .0.4-:25-6mg./ kg. of body weight of active material. The test method used isbasically as described by Spencer, P.S.I., Antagonism of Hypothermia inthe Mouse by Anti-depressants,

in Anti-depressant Drugs, pp. 194-204, Eds. Garattini and M. N. G.Dukes, Excerpta Medica Foundation, 1967.

The compounds of Formulas Ia and lb are also useful as anorexics asindicated by their activity in rat given 10 to 50 mg./kg. of activematerial and tested by use of the free feeding method described byRandall et al. (J .P.E.T., 129, 163, 1960) whereby 16 groups of six maleWistar rats are deprived of food for 18 hours but receive Water adlibitum. Consumption of ground food is then measured over a four hourperiod following oral administration the active compound.

dditionally, the compounds of Formula Ib are useful retics as indicatedby their activity in unanesthetized 11 625-50 mg./kg. and tested usingbasically the sage, Compounds Ia and Th may be admin- I parenterally assuch or admixed with rmaceutical carriers. They may be adsuch forms astablets, dispersible pows, oral suspensions, syrups and elixirs,olutions, suspensions, dispersions, e.g., a sterile injectable aqueousons for oral use may contain cjuvants, such as sweetening ing agents andpreserving gant and palatable prepctive ingredient inadceuticallyacceptable calcium carbonate,

nulating and dis- 'c acid, binding escribed by R. Aston (Toxicol, andAppl. Phar- .wage ts,...e..g-.. starch. gela inan n cia and. ubr cat nagents, e.g., magnesium stearate, stearic acid and talc. The tablets maybe uncoated orcoated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period-Similarly, suspensions, syrups and elixirsmay contain the active ingredient in admixturewith any of theconventional excipients utilized for the preparationof' suchcompositions, e.g., suspending agents (methylcellulose, tragacanth andsodium alginate), wetting agents (lecithin, polyoxyethylene s'tearate"and polyoxyethylene sorbitan monool'eate) "and preservatives(ethyl-p-hydroxybenzoate) Capsules may contain the activeingredientj'alone or'admixe d wan anine'rtsolid'.diluent, e.g.,lcalciuincarbonate, calcium phosphate and kaolin. The injecta bl e compositionsare formulated as known in the art'and may contain appropriatedispersing orjwetting agents and suspending agents identical or similarto those mentioned above. These pharmaceutical preparations may containup to about of the active ingredient in combination-with the carrier oradjuvant. I

9 These compounds-of Formulas- Ia' and lb may be similarly administeredin the form of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the base with an appropriate acid andaccordingly are included within the scope of the invention;Representativebf such salts are'the mineral acid salts, such as thehydrochloride, hydrobromide, sulfate, phosphate and the like andtheorganic acid salts, such as the maleate, fumarate, tartrate, citrate,succinate, benzoate, acetate, ptoluenesulfonate, benzenesulfonate andthe like.

In general, satisfactory results foranorexic or antidepressant activityare obtained when the compounds are administered. at a 'daily dosage'offrom about 0.1 to .50 milligrams perkilogram of animal body' weight.This dail dosage is preferably given in divided doses, e.g., 2 to 4times a day, or in sustained release form. For most large animals, thetotal daily dosage is from aboutd to 300 milligrams and dosage formssuitable 'forinternal administration comprise from about 1.5 to 150milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

For the diuretic use, the Compounds Ib may be administered at a dailydosage of from about 1-5 milligrams per kilogram of animal body weight,preferably given 2-4 times a day or in sustained release form. For mostlarge animals, the total daily dosage is from about 50-500 milligrams,and dosage forms suitable for internal administration comprise fromabout -250 milligrams of Compound Ib in admixture with a solid or liquidpharmaceutical carrier or diluent- Tablets and capsules suitable fororal administration i Tablets and capsules containing the ingredientsindicated below may be prepared by conventional techniques and areuseful in treating depression at a dose of one table or capsule 2 to 4times a day.

' wags; (mg.) l

Ingredient Tm yam nth Tim-rose Copnstarch Sterile suspension forinjection and'oral liquid suspension The followingipharmaceutical' compos'itionsareformulated with'theihdicated amount of active agent usingconventional techniques. The injec'table'suspension and the a Weight(mg) Sterile Oral injcctable liquid Ingredients suspension suspension3-(4-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6- tetrahydroimidazo[2,1-b]thiazole i 25 25 Sodium carboxy methyl cellulose, U.S.P 1. 25 5 Methylcellulose 0.4 Polyvinylpyrrolidone 5 Lecithin 3 Benzyl alcohol 0. 01Magnesium aluminum silicate 47. 5 Flavor. Q.s. Color Q.s. Methylparaben, U.S.P 4. 5 Propyl paraben, U.S.P 1.0 Polysorbate 80 (e.g. Tween80), U.S.P-... 5 Sorbitol solution, 70% U.S.P 2, 500 Buffer agent toadjust pH for desired stability-. Q. .8. Water i) 1 For injection, q.s.to 1 ml. 1 Q.s. to 5 ml.

EXAMPLE 1 3- (4'-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[2,l-b]thiazole hydrobromideA flask (equipped with a stirrer and dropping funnel) is charged with 54g. (0.30 mole) of.4-ch1orobutyro phenone and 250 ml. of chloroform. Thesolution is stirred and a solution of 48.0 g. (16.0 ml., 0.3 mole) ofbromine and 250 ml. of chloroform is added dropwise at a ratesuch thatthe internal flask temperature does not exceed C. The resulting solutionis stirred for one hour and the solvent removed in vacuo. The residue isdissolved in 150 m1. of isopropanol and added in one portion to a slurryof 30.6 g. (0.30 mole) of Z-imidazolinethione and 500 ml. ofisopropanol. The reaction is exothermic and a solution results. In aboutonehour a solid comes out of solution. Stirring is continued for 24hours at room temperature at which time the resultant solid is filteredoil? to give3-(4'-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo [2,1-b]thiazole hydrobromide; M.P.280-283 C.

This compound has been found to have lipolytic activity and may be usedto treat obesity or as a weight reducing agent as indicated by itsactivity in rats given 10- 37.5 mg./kg. of compound and tested asindicated by Dole et al. (J. Biol. Chem. 235; 2595, 1960). This compoundproduces satisfactory results for this use when administered at a dailydosage of from about (LS-37.5 mg./ kg. of animal body weight. For largeanimals, dosages of 15-150 mg./day are satisfactory and dosage forms maycontain about 3.75-75 milligrams of the compound in conjunction withpharmaceutical carrier.

- EXAMPLE 2 A mixture of 30 g. of 3-(4'-chlorophenyl)-2-ethyl-3-hydroxy-Z,3,5,6-tetrahydroimidazo[2,1-b]thiazole hydrobromide and 250m1. acetic acid is refluxed for 15 hours. The solvent is then removed invacuo and the residue is stirred with ml. of isopropanol. The solid isfiltered off to give3-(4'-ch1orophenyl)-2-ethyl-5,6-dihydroimidazo[2,1-b]thiazolehydrobromide; M.P. 281-284 C.

EXAMPLE 3 3-(4 -chlorophenyl)-3-hydroxy-2-methyl-2,3,5,6-tetrahydroimidazo [2, l-b] thiazolehydrobromide Dir A flask (equipped with a stirrer and dropping funnel)is charged with 54 g. (0.30 mole) of 4'-chloropropiophenone and 250 ml.of chloroform. The solution is stirred and a solution of 48.0 g. (16.0ml., 0.3 mole) of bromine and 250 ml. of chloroform is added (dropwise)at a rate such that the internal flask temperature does not exceed 35 C.The resulting solution is stirred for one hour and the solvent removedin vacuo. The residue is dissolved in ml. of isopropanol and added inone portion to a slurry of 30.6 g. (0.30 mole) Z-imidazolinethione and500 ml. of isopropanol. The reaction is exothermic and a solutionresults. In about one hour a solid comes out of solution. Stirring iscontinued for '24 hours at room temperature at which time the resultantsolid is filtered 01f to give 3-(4'-chlorophenyl) 3 hydroxy-2-methyl-2,3,5,6-tetrahydroimidazo[2,1 b]thiazole hydrobromide; M.P.171172 C.

This compound also has lipolytic activity and may be used to treatobesity at the same dosage levels as the com-. pound of Example 1.

When the above process is carried out and 4'-fiuorobutyrophenone, 3,4'dichlorobutyrophenone, 3'-chlorobutyrophenone, -chlorovalerophenone, or4'-chlorohexanophenone is used in place of 4'-chloropropiophen one,there is obtained2-ethyl-3-(4'-fluorophenyl)-3-hydroxy-2,3,5,6-tetrahydroimidazo[2,1-b]thiazolehydrobromide (M.P. -166 C.),

3-( 3 ',4'-dichlorophenyl) -2-ethyl-3-hydroxy-2,3,5,6-

tetrahydroimidazo[2,l-b]thiazole hydrobromide (M.P. 177"-178 C.),

3 3 -chlorophenyl -2-ethyl-3-hydroxy-2,3 ,5,6-tetrahydroimidazo[2,1-b]thiazole hydrobromide (M.P. l79-180 C.),

respectively.

EXAMPLE 4 3- (4'-chlorophenyl -2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobroimide A mixture of 30 g. of 3 (4'chlorophenyl)-3-hydroxy 2 methyl 2,3,5,6 tetrahydroimidazo[2,l-b]thiazole hydrobromide and 250 ml. acetic acid is refluxed for hours. Thesolvent is then removed in vacuo and the residue is stirred with 100 ml.of isopropanol. The solid is filtered olf to give 3 (4'chlorophenyl)-2-methyl- 5,6 dihydroimidazo[2,1-b]thiazole hydrobromide;M.P. 289-290 C.

When the above procedure is carried out and each of the products set outin the last paragraph of Example 3 is used in place of 3 (4'chlorophenyl) 3 hydroxy-Z- methyl-2,3,5,6tetrahydroimidazo[2,l-b]thiazole hydrobromide, there is obtained ml. ofwater. After 1.5 hours stirring the resultant solid is v filtered ofl.to give 3- (4-chlorophenyl) -2-ethyl-3-hydroxy-' 2,3,5,6-'tetrahydroimidazo[2,l b]thiazole; 'M.P. 165- 166 C.

v I I I EXAMPLEG'3-'(4-'-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[2,1-b]thiazolemaleate To a stirred solution of 5.8 g. (0.05 mole) of maleic acid in100 m1. of methanol there is added dropwise' in 0.3

hour a solution of 14.1 g. (0.05 mole) of 3-(4'-chlorophenyl) 2 ethyl3-hydroxy-2,3,5,6-tetrahydroimidazo-- [2,1-b]thiazole in 400 ml. ofmethanol. Afterstirring one hour the solution is concentrated in vacuoto about of the original volume, treated with 300 ml. of diethyl etherand then cooled in an ice bath to obtain 3-(4-chlorophenyl) 2 ethyl 3hydroxy 2,3,5,6 tetrahydroimidazo[2,1-b] thiazole maleate; M.P. 8992" C.u 7

When the above process is carried out and fumaric acid, tartaric acid,hydrochloric acid or citric acid is used in place of maleic acid, thecorresponding fumarate (M.P.

270 272 C.); tartrate (M.P. 128-130 C.), hydrof chloride (M.P. 270-272C.) or citrate (M.P. 146-- 147 C.) respectively, is obtained.

. What is claimed is:

1. A compound of the formula R represents straight chain lower alkyl andR R and R each independently represents hydrogen,

fiuoro or chloro, provided at least one of R R and R is other thanhydrogen, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 which is3-(4'-chlorophenyl)-2-ethyl-5,6-dihydroimidazo [2,1-b] thiazole.

3. The compound of claim 1 which is 3-(4'-chlorophenyl) 2 methyl 5,6dihydroimidazo[2,1-b]thiazole.

4. The compound of claim 1 which is 2 ethyl 3 (4'- fluorophenyl) 5,6dihydroimidazo[2,1-b]thiazole.

5. The compound of claim 1 which is 3 (3',4' dichlorophenyl) 2 ethyl5,6-dihydroimidazo[2,1-b]thiazole.

6. The compound of claim 1 which is 3 (3' chlorophenyl) 2 ethyl 5,6dihydroimidazo[2,1-b]thiazole.

7. The compound of claim 1 which is 3-(4 chlorophenyl) -'2 n propyl 5,6dihydroimidazo[2,1-b] thiazole. j p

T8. The compound of claim 1 which is 2-n-butyl-3- (4'} chlorophenyl) 5,6dihydroimidazo[2,l-b]thiazole.

I References Cited UNITED STATES PATENTS 3,671,533 6/1972 Houlihan etal. 260-3067 RICHARD]. GALLAGHER, Primary Examiner 1' US. 01. X.R.

